The transdermal route of parenteral delivery of drugs provides many advantages, and transdermal systems for delivering a wide variety of drugs are described in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,999; 4,588,580; 4,645,502; 4,704,282; 4,816,258; 4,849,226; 4,908,027; 4,943,435; 5,004,610; 5,006,342; 5,314,694; 5,411,740, 5,629,019; 5,641,504; 5,686,097 for example, all of which are incorporated herein by reference. In many cases, drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they cannot be delivered in therapeutically effective amounts from reasonably sized devices.
In an effort to increase skin permeability so that drugs can be delivered in therapeutically effective amounts, it has been proposed to pretreat the skin with various chemicals or to concurrently deliver the drug in the presence of a permeation enhancer. Various materials have been suggested for this, as described in U.S. Pat. Nos. 3,472,931; 3,527,864; 3,896,238; 3,903,256; 3,952,099; 4,046,886; 4,130,643; 4,130,667; 4,299,826; 4,335,115; 4,343,798; 4,379,454; 4,405,616; 4,568,343; 4,746,515; 4,764,379; 4,788,062; 4,820,720; 4,863,738; 4,863,970; 4,865,848; 4,900,555; 4,940,586; 4,973,468; 5,053,227; 5,059,426; 5,378,730; and WO 95/01167, all of which are hereby incorporated in their entirety by reference. Williams et al. "Skin Absorption Enhancers" Critical Review in Therapeutic Drug Carrier Systems, pp. 305-353 (1992) and Santus et al. "Transdermal Enhancer Patent Literature", Journal of Controlled Release, pp. 1-20 (1993) also provide a recent review of transdermal permeation enhancers.
To be considered useful, a permeation enhancer should have the ability to enhance the permeability of the skin for at least one and preferably a significant number of drugs. More importantly, it should be able to enhance the skin permeability such that the drug delivery rate from a reasonably sized system (preferably 5-60 cm.sup.2) is at therapeutically effective levels. Additionally, the permeation enhancer when applied to the skin surface, should be non-toxic, non-irritating on prolonged exposure and under occlusion, and non-sensitizing on repeated exposure. Preferably, it should be odorless, physiologically inactive, and capable of delivering drugs without producing burning or tingling sensations.
In addition to these permeation enhancer-skin interaction considerations, a permeation enhancer must also be evaluated with respect to possible interactions within the transdermal system itself. For example, the permeation enhancer must be compatible with the drug to be delivered, the adhesive, and the polymer matrix in which the drug is dispersed. The permeation enhancer should also be selected so as to ensure a suitable balance among tack, adhesion, and cohesive strength of the adhesive.
The use of a cosolvent in combination with a permeation enhancer has also been disclosed in the prior art. Such cosolverits may not appreciably increase transdermal flux by themselves, but act synergistically to increase the transdermal flux of a drug when used in combination with other permeation enhancers such as monoglycerides. One theory is that these cosolvents act to increase the availability of the permeation enhancer at the skin surface, thus providing increased flux of drug.
For example, U.S., WO 95/09006 discloses the use of various lactic acid ester cosolvents such as lauryl lactate, ethyl lactate, cetyl lactate, and myristyl lactate in combination with a monoglyceride. However, these lactic acid esters may be irritating to the skin. Further, these lactate esters are not commercially available at a high degree of purity, thus causing regulatory concerns as they are not readily characterized.
WO 96/40259 discloses the use of lauryl acetate as a cosolvent for monoglyceride permeation enhancers such as GML. This combination provides enhanced flux when compared to other monoglyceride/cosolvent combinations and is available at a high degree of purity.
However, lauryl acetate has been found to be an undesirable cosolvent from a manufacturing standpoint. For example, it has been found that an undesirable amount of lauryl acetate evaporates during manufacturing of transdermal systems due to its high vapor pressure, leaving insufficient amounts of lauryl acetate in the system.
Therefore, in spite of these advances, problems associated with skin irritation and more recently discovered problems associated with processing and manufacturing of films comprising various cosolvents for monoglycerides have left a need for improved monoglyceride/cosolvent combinations.
Additionally, U.S. Pat. No. 5,312,122 discloses the use of monoglycerides and fatty acid esters, alone or in combination, as a permeation enhancer mixture for ST 1435, a synthetic progestogen. Specific fatty acid sters or desirable properties are not disclosed.
U.S. Pat. No. 5,026,556 discloses a composition for the transdermal delivery of buprenorphine comprising an amount of buprenorphine in a carrier comprising a polar solvent material selected from the group consisting of C.sub.3 -C.sub.4 diols, C.sub.3 -C.sub.6 triols, and mixtures thereof; and a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures thereof. Ethyl palmitate is disclosed as a suitable polar lipid material.
U.S. Pat. No. 5,352,456 discloses a transdermal device which provides an initial pulse of drug followed by a substantially lower continues rate. The device comprises a drug reservoir comprising the drug dissolved in a carrier and a volatile permeation enhancer. The volatile permeation enhancer is depleted from the reservoir by evaporation through the backing layer causing the decrease in drug delivery rate. The volatile permeation enhancers are described as comprising a vapor pressure of greater than about 10 mm Hg at 25.degree. C.
U.S. Pat. No. 5,149,538 discloses the transdermal delivery of an opioid. Preferred permeation enhancers are saturated and unsaturated fatty alcohols, fatty alcohol esters, or fatty acids having 8-18 carbon atoms.
U.S. Pat. No. 5,650,165 discloses percutaneous absorption preparations comprising an acrylic copolymer, a fatty acid ester comprising a higher fatty acid having 12-16 carbon atoms and a lower monohydric alcohol having 1-4 carbon atoms, and a monoglyceride comprising a higher fatty acid having 8-10 carbon atoms.
U.S. Pat. No. 5,747,069 discloses a percutaneous absorbable preparation containing a drug and an absorption accelerator comprising a monoglyceride and a fatty acid. All of the aforementioned patents are incorporated herein in their entirety by reference.